T-cell-mediated immunity to SARS-CoV-2 defines COVID-19 risk and severity in transplanted and non-transplanted individuals and associates with myeloid-derived suppressor cells

ABSTRACT

Purpose: We assessed whether COVID-19-risk is enhanced by chronic immunosuppression, and is associated with suppressor cells. Methods: We tested 66 COVID-19 patients, including 26 with solid organ transplants at median 11 days after diagnosis, and 64 unexposed healthy subjects including 21 with transplants, who were sampled pre-pandemic. T- and B-cells, which express CD154 were measured after stimulation with peptide mixtures representing the spike protein S, its conserved C-terminal S2, and less conserved N-terminal S1 components. Monocytic myeloid-derived suppressor cells (M-MDSC) were measured in an independent cohort of 47 COVID-19 patients Results: Frequencies (%) of S-reactive T-cells (Mean±SEM 2.0±0.3 vs 3.8±0.3, p=5.6E-05) and B-cells (3.0±0.4 vs 5.1±0.4, p=0.0003) were significantly lower in COVID-19 compared with healthy subjects, but were measurable in all samples. Transplanted and non-transplanted subjects demonstrated similar within group frequencies of S-reactive T-cells (4.1±0.3 vs 3.7±0.5, p=NS in healthy and 1.5±0.4 vs 2.4±0.3, p=NS in the COVID-19 group) and other S-reactive cells. Among COVID-19 patients, intubated patients showed lower S-reactive CD8 frequencies compared with non-intubated patients. (1.4±0.5 vs 3.5±0.5, p=0.003). In logistic regression analysis using training and test sets, S-reactive CD3 and CD8 cells, age, race, and transplantation status distinguished COVID-19 from healthy subjects (test set negative and positive predictive values 75% and 85% respectively, AUC 0.9). Among 66 COVID-19 patients, S-reactive CD8 cells and age predicted respiratory failure with NPV 62%, PPV 86%, AUC 0.73. S2-reactive T-cells demonstrated similar predictive performance. S1 antigen elicited minimal cellular responses. Transplanted COVID-19 patients show lower cytomegalovirus-specific CD154+CD3 frequencies compared with non-transplanted patients (0.5±0.1 vs 1.3±0.2, p=0.006). Frequencies of CD14+CD33+CD11b+HLADR-ve M-MDSC (14.5±2.9 vs 3.3±1.5, p=0.002) were higher in 47 independent COVID-19 patients compared with 6 healthy subjects. Conclusions: Conserved SARS-CoV-2-spike antigen drives T-cell immunity to COVID-19 in unexposed transplanted and non-transplanted subjects. This immunity declines with COVID-19 infection, is accompanied by increased myeloid derived suppressor cells, and can predict infection-risk and disease severity. Transplant patients demonstrate increased COVID-19-risk and co-infection-risk.